Many dangerous diseases in humans and animals are known to be caused by bacteria and viruses. Bacteria cause such epidemic diseases as cholera, typhoid fever, paratyphoid fever, plague, diphtheria, tularemia, brucellosis, as well as tuberculosis, septicemia (blood poisoning), leprosy, syphilis, and others. In animals, bacteria cause equinia, anthrax, tuberculosis, and other diseases. Strategy in the fight against microorganisms involves the administration of antibacterial agents, including antibiotics. However, many known agents suffer from drawbacks such as toxicity, sensitivity to proteolytic enzymes, a hemolytic effect, and an insufficient range of antibacterial activity. Consistent development of resistant strains, i.e. strains resistant to known antibacterial agents, is a serious problem. Thus at the moment, for example, methicillin-resistant staphylococcus (MRSA) which is resistant to a large group of beta-lactam antibiotics currently is most dangerous. Methicillin-resistant staphylococcus causes difficult-to-treat diseases in humans such as blood diseases and pneumonia. It has adapted to methicillin, difloxacin, and oxacillin. This pathogen is often associated with nosocomial infections. Each year more than 18,000 American patients die from methicillin-resistant staphylococcus infections.
In this context, a search for novel antibacterial agents, including those that are active against resistant strains is still of great interest.
Viruses also cause different diseases, such as influenza, acute respiratory viral infection (ARVI), viral hepatitis, etc. Herpes Simplex viruses are the most known representatives of herpesviruses (the family Herpesviridae) since they infect almost every person. There are two types of herpes simplex viruses (HSV)—HSV-1 (oral herpes) and HSV-2 (genital herpes). Herpes viruses can affect the nervous system, eyes and internal organs. Herpes virus is the most common cause of acute viral encephalitis in the U.S. Herpes Simplex virus type 1 is a causative agent in more than 95% of herpes encephalitis cases. Acyclovir is a well-known agent against herpes viruses. However, since acyclovir-resistant herpes virus strains already exist, a search for novel anti-herpetic agents is still of current interest.
Hemin is known to have an antimicrobial activity against Staphylococcus aureus [Y. Nitzan, H. Ladan, S. Gozansky, and Z. Malik, “Characterization of Hemin Antibacterial Action on Staphylococcus aureus,” FEMS Microbiol. Lett., 1987, Vol. 48(3), pp. 401-406]. However, the use of hemin as an antibacterial agent is hampered by its water insolubility, hemolytic activity, and short-term antibacterial effect.
Efforts were undertaken to modify hemin by the conjugation thereof with amino acids, peptides and derivatives thereof to produce biologically active derivatives. The modification of the hemin carboxy groups to prepare the corresponding amides resulted in compounds, which were studied, of general formula (I)
wherein R1 and R2, are the same or different, representing —OH or an amino acid or peptide moiety, and wherein R1 and R2 cannot simultaneously be —OH. Men+ is Fe2+ or Fe3+; Hal− is F−, Cl−, Br− or I−, [RU patent No. 2250906, published on Apr. 27, 2005]. These derivatives have been found to manifest various biological activities, including nuclease [RU patent No. 2404191, published on Nov. 20, 2010], [RU patent No. 2250906, published on Apr. 27, 2005], peroxidase, catalytic [RU patent No. 2404191, published on Nov. 20, 2010], and virulicide activities [RU patent No. 2404191, published on Nov. 20, 2010].
Among the hemin derivatives that have been synthesized earlier by the present inventors there are a number of specific compounds exhibiting an antimicrobial (including antibacterial) activity [RU patent No. 2415868 C1, published on Apr. 10, 2011]. These compounds mainly represent conjugates of hemin with amino acid esters and antimicrobial peptides, where hemin derivatives wherein in particular, R1=R2=-GlyOMe, R1=R2=—NHCH2CH2OH, SerOMe or -Glu(ArgOMe)-ArgOMe, have been found to possess antibacterial activity. However, only a few number of hemin derivatives were found to be effective against resistant bacterial strains, which derivatives are also hardly soluble in water and have a lower activity.
At the moment, novel hemin derivatives have been found, which demonstrate antibacterial and antiviral activities and have improved properties, in particular, possess activity against MRSA strains.